The major objectives of the present study are to determine the nature of proteins forming intracellular complexes with potentially toxic metals (lead and mercury), the functional changes in the cell containing intranuclear inclusions and the effect of chelating agents in tissue culture to remove the metal. These metals are known to bind intracellularly with acidic nuclear proteins, but it is not known whether these proteins are synthesized specifically for binding with these metals. Experiments are planned to study the de novo synthesis of these proteins in response to metals and the effect of metabolic inhibitors of protein synthesis (cycloheximide or actinomycin D). If the formation of nuclear inclusions can be inhibited, the toxic effects of the same amount of metal will be compared in pretreated and control rats. The functional activity of hepatic cells from these two groups of rats to synthesize and secrete albumin will be compared in tissue culture system. If protein-metal complexing does not have any adverse effect, possible induction of these proteins will be studied by prior exposure to less toxic essential metals, zinc and/or copper. The effect of chelating agents, EDTA, BAL, ascorbic acid and dimercapto succinic acid (DMSA) in removing metals from the cell nucleus will be studied in cell culture. The proposed studies will increase our understanding (1) Variation in susceptibility of different individuals in the population to the toxic effects of metals in industrial exposure or in the ambient environment, (2) may determine possible ways of inducing protective metal-binding proteins by administration of less toxic metals, (3) effects of chelating agents, and (4) functional changes of cell induced by nuclear inclusions.